Project Summary Psychiatric Genomics Consortium for PTSD Post-traumatic stress disorder (PTSD) occurs only in vulnerable individuals after exposure to severe traumatic events. This risk is due, in part, to 40-70% heritability of differential vulnerability or resilience. In fact, recent studies have suggested that the heritability for PTSD may be twice that of Major Depressive Disorder. Due to increasing collaborations across the field of PTSD genomics, it is a very exciting time for discovering the underlying genetic risk factors contributing to PTSD. The purpose of this application is to facilitate meta- analyses of genome-wide association study (GWAS) data for symptoms and diagnosis of PTSD. We propose to conduct this first large-scale meta-analysis through the PTSD group of the Psychiatric Genomics Consortium (PGC). The PGC was created in 2007 to conduct field-wide mega-analyses of individual data for five major psychiatric disorders. It united the field for the first time, and it is the largest consortium (>500 scientists from >80 institutions in 25 countries) in the history of psychiatry. The PGC has already produced three major findings with regard to the genetic architecture of psychiatric disorders. First, reliable associations can be identified with extremely large sample sizes. A meta-analysis of GWAS in SCZ has produced over 100 loci at the genome-wide significance threshold in a sample of 36,000 cases and 43,000 controls. Second, the polygenic architecture inferred from family studies was confirmed with molecular evidence, and refined via demonstration of substantial effects of both common and rare variants. Third, confirming findings from twin studies, there are shared genetic contributions among psychiatric disorders. The PGC-PTSD group was launched in May 2013 and since then has been enormously successful, with over 25 investigators contributing genotype data from over 20 studies with a total N of over 76,000 combined cases and trauma-exposed controls. We also have commitments of collaborations using ~ 77,000 additional cases and controls from banked samples from over 20 studies, and our progress thus far demonstrates feasibility of the proposed work. We hypothesize that with well-powered, large sample-size studies, along with a deeply phenotyped set of cohorts, the PGC-PTSD group can identify the genetic architecture of PTSD. We will test this hypothesis through our Primary Aim focusing on detecting novel genetic variation associated with risk for PTSD. The primary aim of this study is to detect novel genetic variants (SNPs and CNVs) that predict the development of PTSD following trauma. We will conduct the study in three stages ? discovery, biological annotation, and replication. This aim will be supplemented by Exploratory Aims which will expand the genomic approaches to include GxE analyses, meta-analyses of intermediate phenotypes, and cross disorder polygenic risk score analyses. Identifying the genetic pathways underlying PTSD will lead to an improved neurobiological understanding, enhanced prevention, and improved treatment of this debilitating and prevalent syndrome.